Abnormalities of pulmonary artery pressure and resistance continue to complicate many varieties of cardiovascular problems in childhood. Much recent effort has been devoted to understanding the cellular mechanisms underlying the pathophysiology of pulmonary hypertension, centering on endothelial cell dysfunction as a principal factor. Defects in the vasodilation machinery of the endothelial cell, such as overexpression of vasoconstrictor elements, have been implicated in various forms of pulmonary hypertension. This includes pulmonary hypertension that is secondary to congenital heart disease, and the primary forms that occur in older children and in neonates. In addition, experimental methods assessing cyclic adenosine monophosphate-mediated and cyclic guanosine monophosphate-mediated vasoreactivity suggest a possible genetic basis in the responses of the pulmonary microvasculature. This article reviews some of the current information that has been developed along these lines, and explores the implications of these data for therapeutic strategies to treat this complex problem.